Compounds characterised by the combination of an indole ring system and a 2,3-dihydro-1,4-benzodioxin ring system have been described for their serotonin-reuptake inhibiting properties (WO 9717343). Indoles substituted on the aromatic moiety have also been claimed in Patent Application EP 814 084 for their action at the level of the serotonin-reuptake sites. Other compounds having related properties have been claimed in Patent Application WO 9633710 and have a benzopyran structure.
Serotonin-reuptake inhibitors constitute a heterogeneous group of therapeutic agents. They are used in the treatment of pathologies associated with a serotonin deficit at the level of the central neurone synapses. The inhibition of serotonin reuptake by binding to transporters or presynaptic receptors is a means of restoring nerve transmission.
The use of compounds having those inhibitory properties may constitute an alternative to the use of tricyclic antidepressants or of monoamine oxidase inhibitors in the treatment of depression and associated disorders (Annals of Pharmacotherapy, 1994, 28, 1359), panic attacks and obsessive-compulsive disorders (Human Psychopharmacology, 1995, 10, 5199). The efficacy of compounds having such pharmacological properties (Journal of Psychopharmacology, 1994, 8, 238) is reinforced by the fact that they are better tolerated (International Clinical Psychopharmacology, 1995, 9 suppl. 4, 33) and are safer to use (Annals of Pharmacology, reference cited).
The compounds of the present invention are characterised by an indole ring system substituted on the benzene moiety by a cyano group and in the 3-position by an N-substituted 3-pyrrolylalkyl group. That novel structure confers upon them a powerful serotonin-reuptake inhibiting character. They will therefore be useful therapeutically in the treatment of depression, panic attacks, obsessive-compulsive disorders, phobias, impulsive disorders associated with drug abuse, bulimia nervosa and anxiety.
The present invention relates to compounds of formula (I): 
wherein:
R1 and R2 each independently of the other represents a hydrogen atom or a linear or branched (C1-C6)alkyl group,
T1 and T2 each independently of the other represents a linear or branched (C1-C6)-alkylene group,
G represents a heterocyclic group of formula (xcex1) or (xcex2): 
xe2x80x83wherein:
W1 to W5 and X1 to X4 are so selected as to form a chemically stable group and are defined as follows:
W1, W2 and W3 each independently of the others represents a nitrogen atom or a group CR5, NR4 or CO,
W4 represents a nitrogen atom or a group CR3, NR4 or CO,
W5 represents a carbon atom or a nitrogen atom,
X1 represents a bond, a nitrogen atom or a group CR3 or NR4,
X2 to X4 each independently of the others represents a group CR3, NR4, CO, SR4 or SO2 or an oxygen, sulphur or nitrogen atom,
R3 represents a hydrogen or halogen atom or a linear or branched (C1-C6)alkyl group, hydroxy group, linear or branched (C1-C6)perhaloalkyl group, nitro group, or amino group (optionally substituted by one or two groups selected from linear or branched (C1-C6)alkyl and benzyl),
R4 represents a hydrogen atom or a linear or branched (C1-C6)alkyl group, optionally substituted aryl group or optionally substituted arylalkyl group,
R5 represents a group R3, or two adjacent groups R5 form, together with the carbon atoms carrying them, a saturated, partially unsaturated or unsaturated mono- or bi-cyclic group optionally containing from 1 to 5 hetero atoms selected from nitrogen, oxygen and sulphur, the said group being optionally substituted by one or more groups selected from R3 and oxo,
xe2x80x83it being understood that, in formulae (xcex1) and (xcex2), at least one heteroatom is present, the dotted lines indicate that the groups in question may contain an unsaturated bond or a plurality of conjugated or unconjugated unsaturated bonds and that, if there is no unsaturated bond, the remaining valences are occupied by hydrogen atoms, the groups (xcex1) and (xcex2) being linked to T2 by any one of their ring junctions,
their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.
Among the pharmaceutically acceptable acids there may be mentioned, by way of non-limiting examples, hydrochloric acid, hydrobromic acid, sulphuric acid, phosphonic acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, methanesulphonic acid, camphoric acid etc.
Among the pharmaceutically acceptable bases there may be mentioned, by way of non-limiting examples, sodium hydroxide, potassium hydroxide, triethylamine, tert-butylamine etc.
An aryl group is understood to mean a phenyl or naphthyl group.
The expression xe2x80x9coptionally substitutedxe2x80x9d applied to aryl or arylalkyl groups means that the groups in question are optionally substituted by one or more groups selected from halogen atoms, linear or branched (C1-C6)alkyl groups, hydroxy groups, linear or branched (C1-C6)perhaloalkyl groups, nitro groups, and amino groups (optionally substituted by one or two groups selected from linear or branched (C1-C6)alkyl and benzyl).
Advantageously, the invention relates to compounds of formula (I) wherein the cyano group is attached in the 5-position of the indole ring system.
Another advantageous aspect of the invention relates to compounds of formula (I) wherein the cyano group is attached in the 6-position of the indole ring system.
Preferably, in the compounds of formula (I) R1 and R2 each represents a hydrogen atom.
Preferred compounds of the invention are those wherein T1 represents a methylene group.
The preferred aryl group of the invention is the phenyl group. In preferred groups G of the invention, R3, R4 and R5 are advantageously selected from linear or branched (C1-C6)alkyl groups, hydrogen atoms and halogen atoms.
Among preferred groups G of the invention there may be mentioned, without implying any limitation, the groups:
2-furyl; 2,4-dioxo-1,4-dihydro-3(2H)-quinazolinyl; 3-oxo-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl; 1-oxo-2(1H)-phthalazinyl; 7-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyridin-6-yl; 6-chloro-2-oxo-2,3-dihydro-1H-indol-5-yl; 2-oxo-2,3-dihydro-1H-indol-5-yl; 2-oxo-1,2,3,4-tetrahydro-6-quinolinyl; 3-benzyl-5-methyl-2,6-dioxo-3,6-dihydro-1(2H)-pyrimidinyl; 1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl; 1,1,3-trioxo-1,3-dihydro-2H-1,2-benzisothiazol-2-yl; 1,3-dioxo-3,6-dihydropyrrolo[3,4-c]carbazol-2(1H)-yl; 1,3-dioxo-1,3-dihydro-2H-benzo[c]isoindol-2-yl; 3,5-dimethyl-2,6-dioxo-3,6-dihydro-1(2H)-pyrimidinyl.
An especially advantageous aspect of the invention relates to compounds of formula (I) wherein R1 and R2 each represents a hydrogen atom, T1 represents a methylene group, T2 represents an alkylene group (for example methylene or ethylene) and G is selected from the groups 2-furyl; 2,4-dioxo-1,4-dihydro-3(2H)-quinazolinyl; 3-oxo-[1,2,4]triazolo-[4,3-a]pyridin-2(3H)-yl; 1-oxo-2(1H)-phthalazinyl; 7-methyl-5-oxo-5H-[1,3]thiazolo-[3,2-a]pyrimidin-6-yl; 6-chloro-2-oxo-2,3-dihydro-1H-indol-5-yl; 2-oxo-2,3-dihydro-1H- indol-5-yl; 2-oxo-1,2,3,4-tetrahydro-6-quinolinyl; 3-benzyl-5-methyl-2,6-dioxo-3,6-dihydro-1(2H)-pyrimidinyl; 1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl; 1,1,3-trioxo-1,3-dihydro-2H-1,2-benzisothiazol-2-yl; 1,3-dioxo-3,6-dihydropyrrolo[3,4-c]carbazol-2(1H)-yl; 1,3-dioxo-1,3-dihydro-2H-benzo[c]isoindol-2-yl; 3,5-dimethyl-2,6-dioxo-3,6-dihydro-1(2H)-pyrimidinyl.
Among those compounds preference will be given to those wherein the cyano group is attached in the 5- or 6-position of the indole ring system, more especially those wherein the cyano group is attached in the 5-position.
Among the preferred compounds of the invention, there may be mentioned more especially:
3-({1-[2-(7-methyl-5-oxo-5H)-[1,3]thiazolo[3,2-a]pyrimidin-6-yl)ethyl]-3-pyrrolidinyl}methyl)-1H-indole-5-carbonitrile hydrochloride
3-({1-[2-(6-chloro-2-oxo-2,3-dihydro-1H-indol-5-yl)ethyl]-3-pyrrolidinyl}methyl)-1H-indole-5-carbonitrile hydrochloride.
The invention relates also to a process for the preparation of compounds of formula (I), which process is characterised in that there is used as starting material a compound of formula (II): 
wherein R1, R2 and T1 are as defined for formula (I),
which is subjected:
either to the action, in a reducing medium, of an aldehyde of formula (III):
OHCxe2x80x94Txe2x80x22xe2x80x94Gxe2x80x83xe2x80x83(III)
wherein G is as defined for formula (I) and Txe2x80x22 represents a bond or a linear or branched (C1-C5)alkylene group,
or to the action, in a basic medium, of a halogenated compound of formula (IV):
Halxe2x80x94T2xe2x80x94Gxe2x80x83xe2x80x83(IV)
wherein T2 is as defined for formula (I) and Hal represents a halogen atom,
to yield a compound of formula (I),
or which is subjected to the action, in a basic medium, of a compound of formula (V):
Halxe2x80x94T2xe2x80x94NHxe2x80x94Pxe2x80x2xe2x80x83xe2x80x83(V)
wherein T2 is as defined for formula (I), Hal represents a halogen atom and Pxe2x80x2 is a protecting group for the amine,
to yield a compound of formula (VI), 
wherein R1, R2, T1, T2 and Pxe2x80x2 are as defined hereinbefore,
which compound of formula (VI), after deprotection of the primary amine group, is condensed with a cyclic group that is a precursor of group G defined for formula (I) to yield a compound of formula (I/a): 
a particular case of the compounds of formula (I) wherein R1, R2, T1 and T2 are as defined hereinbefore and Gxe2x80x2 represents a group as defined for G in formula (I), it being understood that Gxe2x80x2 is attached to T2 by a nitrogen atom,
which compounds of formulae (I/a) and (I),
may be purified, if necessary, according to a conventional purification technique,
are separated, where appropriate, into their isomers according to a conventional separation technique,
are converted, if desired, into addition salts thereof with a pharmaceutically acceptable acid or base.
The present invention relates also to pharmaceutical compositions comprising as active ingredient at least one compound of formula (I), alone or in combination with one or more inert, non-toxic pharmaceutically acceptable excipients or carriers.
Among the pharmaceutical compositions according to the invention there may be mentioned more especially those that are suitable for oral, parenteral or nasal administration, tablets or dragees, sublingual tablets, gelatin capsules, lozenges, suppositories, creams, ointments, dermal gels etc.
The useful dosage varies according to the age and weight of the patient, the nature and severity of the disorder and the route of administration, which may be oral, nasal, rectal or parenteral. The unit dose generally ranges from 0.1 to 500 mg for a treatment in from 1 to 3 administrations per 24 hours.